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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-stage Anti-Malarial Compounds</title><author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name><affiliation><nlm:aff id="A2"> Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation></author><author><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Blundell, Scott" sort="Blundell, Scott" uniqKey="Blundell S" first="Scott" last="Blundell">Scott Blundell</name><affiliation><nlm:aff id="A4"> Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Liu, Feng" sort="Liu, Feng" uniqKey="Liu F" first="Feng" last="Liu">Feng Liu</name><affiliation><nlm:aff id="A5"> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation></author><author><name sortKey="Chen, Xin" sort="Chen, Xin" uniqKey="Chen X" first="Xin" last="Chen">Xin Chen</name><affiliation><nlm:aff id="A5"> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation></author><author><name sortKey="Srimongkolpithak, Nitipol" sort="Srimongkolpithak, Nitipol" uniqKey="Srimongkolpithak N" first="Nitipol" last="Srimongkolpithak">Nitipol Srimongkolpithak</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Jin, Jian" sort="Jin, Jian" uniqKey="Jin J" first="Jian" last="Jin">Jian Jin</name><affiliation><nlm:aff id="A5"> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A6"> Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation></author><author><name sortKey="Charman, Susan A" sort="Charman, Susan A" uniqKey="Charman S" first="Susan A." last="Charman">Susan A. Charman</name><affiliation><nlm:aff id="A4"> Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name><affiliation><nlm:aff id="A2"> Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation></author><author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25044750</idno><idno type="pmc">4177335</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177335</idno><idno type="RBID">PMC:4177335</idno><idno type="doi">10.1002/cmdc.201402098</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001E39</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001E39</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-stage Anti-Malarial Compounds</title><author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name><affiliation><nlm:aff id="A2"> Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation></author><author><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Blundell, Scott" sort="Blundell, Scott" uniqKey="Blundell S" first="Scott" last="Blundell">Scott Blundell</name><affiliation><nlm:aff id="A4"> Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Liu, Feng" sort="Liu, Feng" uniqKey="Liu F" first="Feng" last="Liu">Feng Liu</name><affiliation><nlm:aff id="A5"> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation></author><author><name sortKey="Chen, Xin" sort="Chen, Xin" uniqKey="Chen X" first="Xin" last="Chen">Xin Chen</name><affiliation><nlm:aff id="A5"> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation></author><author><name sortKey="Srimongkolpithak, Nitipol" sort="Srimongkolpithak, Nitipol" uniqKey="Srimongkolpithak N" first="Nitipol" last="Srimongkolpithak">Nitipol Srimongkolpithak</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Jin, Jian" sort="Jin, Jian" uniqKey="Jin J" first="Jian" last="Jin">Jian Jin</name><affiliation><nlm:aff id="A5"> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A6"> Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States</nlm:aff></affiliation></author><author><name sortKey="Charman, Susan A" sort="Charman, Susan A" uniqKey="Charman S" first="Susan A." last="Charman">Susan A. Charman</name><affiliation><nlm:aff id="A4"> Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia</nlm:aff></affiliation></author><author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name><affiliation><nlm:aff id="A2"> Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France</nlm:aff></affiliation></author><author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J." last="Fuchter">Matthew J. Fuchter</name><affiliation><nlm:aff id="A1"> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</nlm:aff></affiliation></author></analytic><series><title level="j">ChemMedChem</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent <italic>in vitro</italic> and <italic>in vivo</italic> antimalarial activity of BIX01294 (<bold>1</bold>), a known human G9a inhibitor, together with its dose-dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimize the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core and these molecules were tested against <italic>Plasmodium falciparum</italic> (3D7 strain). Several analogues with IC<sub>50</sub> values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for the antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and the human HKMT targets of this chemotype. Physiochemical, <italic>in vitro</italic> activity, and <italic>in vitro</italic> metabolism studies were also performed for a select set of potent analogues to evaluate their potential as anti-malarial leads.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101259013</journal-id><journal-id journal-id-type="pubmed-jr-id">33017</journal-id><journal-id journal-id-type="nlm-ta">ChemMedChem</journal-id><journal-id journal-id-type="iso-abbrev">ChemMedChem</journal-id><journal-title-group><journal-title>ChemMedChem</journal-title></journal-title-group><issn pub-type="ppub">1860-7179</issn><issn pub-type="epub">1860-7187</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25044750</article-id><article-id pub-id-type="pmc">4177335</article-id><article-id pub-id-type="doi">10.1002/cmdc.201402098</article-id><article-id pub-id-type="manuscript">NIHMS626793</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-stage Anti-Malarial Compounds</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Sundriyal</surname><given-names>Sandeep</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Malmquist</surname><given-names>Nicholas A.</given-names></name><xref ref-type="aff" rid="A2">b</xref><xref ref-type="aff" rid="A3">c</xref></contrib><contrib contrib-type="author"><name><surname>Caron</surname><given-names>Joachim</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Blundell</surname><given-names>Scott</given-names></name><xref ref-type="aff" rid="A4">d</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Feng</given-names></name><xref ref-type="aff" rid="A5">e</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Xin</given-names></name><xref ref-type="aff" rid="A5">e</xref></contrib><contrib contrib-type="author"><name><surname>Srimongkolpithak</surname><given-names>Nitipol</given-names></name><xref ref-type="aff" rid="A1">a</xref></contrib><contrib contrib-type="author"><name><surname>Jin</surname><given-names>Jian</given-names></name><xref ref-type="aff" rid="A5">e</xref><xref ref-type="aff" rid="A6">f</xref></contrib><contrib contrib-type="author"><name><surname>Charman</surname><given-names>Susan A.</given-names></name><xref ref-type="aff" rid="A4">d</xref></contrib><contrib contrib-type="author"><name><surname>Scherf</surname><given-names>Artur</given-names></name><xref ref-type="aff" rid="A2">b</xref><xref ref-type="aff" rid="A3">c</xref></contrib><contrib contrib-type="author"><name><surname>Fuchter</surname><given-names>Matthew J.</given-names></name><xref ref-type="corresp" rid="CR1">*</xref><xref ref-type="aff" rid="A1">a</xref></contrib></contrib-group><aff id="A1"><label>a</label> Department of Chemistry, Imperial College London, London SW7 2AZ, United Kingdom</aff><aff id="A2"><label>b</label> Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, F-75724 Paris CEDEX 15, France</aff><aff id="A3"><label>c</label> Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, F-75724 Paris CEDEX 15, France</aff><aff id="A4"><label>d</label> Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, Victoria 3052, Australia</aff><aff id="A5"><label>e</label> Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 26 Chapel Hill, North Carolina 27599, United States</aff><aff id="A6"><label>f</label> Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States</aff><author-notes><corresp id="CR1"><label>*</label><email>m.fuchter@imperial.ac.uk</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>16</day><month>9</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>09</day><month>7</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>10</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>10</month><year>2015</year></pub-date><volume>9</volume><issue>10</issue><fpage>2360</fpage><lpage>2373</lpage><pmc-comment>elocation-id from pubmed: 10.1002/cmdc.201402098</pmc-comment>
<abstract><p id="P1">Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent <italic>in vitro</italic> and <italic>in vivo</italic> antimalarial activity of BIX01294 (<bold>1</bold>), a known human G9a inhibitor, together with its dose-dependent effects on histone methylation in the malarial parasite. This work describes our initial medicinal chemistry efforts to optimize the diaminoquinazoline chemotype for antimalarial activity. A variety of analogues were designed by substituting the 2 and 4 positions of the quinazoline core and these molecules were tested against <italic>Plasmodium falciparum</italic> (3D7 strain). Several analogues with IC<sub>50</sub> values as low as 18.5 nM and with low mammalian cell toxicity (HepG2) were identified. Certain pharmacophoric features required for the antimalarial activity were found to be analogous to the previously published SAR of these analogues for G9a inhibition, thereby suggesting potential similarities between the malarial and the human HKMT targets of this chemotype. Physiochemical, <italic>in vitro</italic> activity, and <italic>in vitro</italic> metabolism studies were also performed for a select set of potent analogues to evaluate their potential as anti-malarial leads.</p></abstract><kwd-group><kwd>Drug Design</kwd><kwd>Structure-Activity Relationships</kwd><kwd>Histone methyltransferase</kwd><kwd>malaria</kwd><kwd>diaminoquinazoline</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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